Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination

Abstract

Objective: We investigated mitochondrial DNA (mtDNA) variants in children with a first episode of acquired demyelinating syndromes (PD-ADS) of the CNS and their relationship to disease phenotype, including subsequent diagnosis of multiple sclerosis (MS).Methods: This exploratory analysis included the initial 213 children with PD-ADS in the prospective Canadian Pediatric Demyelinating Study and 166 matched healthy sibling controls from the Canadian Autism Genome Project. A total of 31 single nucleotide polymorphisms (SNPs) were analyzed, including haplogroup-defining SNPs and mtDNA variants previously reported to be associated with MS. Results: Primary Leber hereditary optic neuropathy (LHON) mutations and other known patho-genic mtDNA mutations were absent in both patients with pediatric acquired demyelinating syndromes and controls. The 13708A haplogroup J-associated variant, previously linked to adult MS, was more frequent among subjects with PD-ADS (13.0%) compared to controls (6.2%; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.06 to 4.83) and haplogroup M was associated with an earlier age at onset of PD-ADS (Ϫ1.74 years; 95% CI Ϫ3.33 to Ϫ0.07). In contrast, the haplogroup cluster UKJT, as well as 3 other SNPs, were each associated with a lower risk of PD-ADS. A total of 33 subjects with PD-ADS were diagnosed with MS during a mean follow-up period of 3.11 Ϯ 1.14 (SD) years. No single SNP was associated with the risk of subsequent diagnosis of MS. However, haplogroup H was associated with an increased risk of MS (OR 2.60; 95% CI 1.21 to 5.55). Conclusion:These data suggest an association between mtDNA variants and the risk of PD-ADS and of a subsequent MS diagnosis. Replication of these findings in an independent population of subjects with PD-ADS is required. Neurology ® 2011;76:774-780 GLOSSARY ADEM ϭ acute disseminated encephalomyelitis; ADS ϭ acquired demyelinating syndrome; CI ϭ confidence interval; LHON ϭ Leber hereditary optic neuropathy; MS ϭ multiple sclerosis; mtDNA ϭ mitochondrial DNA; OR ϭ odds ratio; PD-ADS ϭ first episode of acquired demyelinating syndrome; SNP ϭ single nucleotide polymorphism.

Mitochondrial DNA sequence variation in multiple sclerosis

“…By sequencing a subset of study participants, the authors concluded that the association is due to m.13708G.A and not the other haplogroup J SNPs (including m.295C.T) linked to this variant. The m.13708G.A variant was also significantly associated with pediatric acquired demyelination syndrome (PD-ADS), 23 providing further evidence to suggest that m.13708G.A is the SNP underlying the haplogroup J associations with MS and PPMS identified in the current study.…”

Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER

“…Previous studies have found haplogroup J and multi-haplogroup categories that include J to be associated with decreased prevalence of Parkinson’s disease (Van Der Walt et al, 2003), neuroretinal disorder in HIV patients (Hendrickson et al, 2010), and acquired demyelinating syndrome (Venkateswaran et al, 2011). Conversely, findings from other studies suggest that haplogroup J is a risk factor for or not associated with these and other neurologic disorders (Jones et al, 2007; Kalman et al, 1999; Mehta et al, 2009; Reynier et al, 1999; Ross et al, 2003).…”

Do old HLA and mitochondrial DNA variants associate with demyelination types in young patients?

“…The investigators assessed nuclear (DRB1*1501) 1 and mitochondrial (various) 2 genetic variants in pediatric patients who present with acquired demyelinating syndromes. Two articles from the Canadian Pediatric Demyelinating Disease Network in the current issue of Neurology ® consider the frequency of 2 different putative biomarkers.…”

“…2 The study evaluated a similar cohort of pediatric patients with acquired demyelinating syndromes. 2 The study evaluated a similar cohort of pediatric patients with acquired demyelinating syndromes.…”

“…2 The analysis of Caucasian mtDNA haplogroups in cohorts with ethnic heterogeneity involves some interpretive difficulties since mtDNA variants align in haplotypes and haplogroups in phylogenetic trees in an ethnic specific manner. The statistical significance was mostly borderline.…”